Each year gallstone disease inflicts large numbers of individuals worldwide. The disease is characterized by biliary colic and is frequently accompanied by obstructive jaundice or pancreatitis. Additionally, patients may experience nausea and vomiting as well as extreme abdominal pain and tenderness. These symptoms are attributed to the presence of calculi, known as biliary tract stones, or gallstones, in the gallbladder or other parts of the biliary tract. A traditional method for treating gallstone disease is to surgically remove the gallbladder with the problematic gallstones remaining intact inside the extracted gallbladder. This procedure, known as cholecystectomy, involves major abdominal surgery and many gallstone disease patients can neither tolerate the surgical intervention nor the traumatic recovery associated with the surgery. Additionally, the high cost of cholecystectomies and long post surgery recovery times make this procedure particularly unattractive.
In recent years many medical practioners have turned to treatment procedures known as cholelitholysis, or methods for chemically dissolving gallstones. These dissolution techniques initially targeted gallstones having high cholesterol contents. Typically, gallstones suitable for cholelitholysis are at least 75% and generally over 80% cholesterol. One such cholesterol gallstone dissolution method involves orally administering bile acids to patients known to have mostly cholesterol gallstones. This procedure has enjoyed only limited success, and a majority of the patients do not experience complete gallstone dissolution. Moreover, signs of effective gallstone dissolution generally are not apparent until after many months of treatment. Additionally, this method is not practical for patients suffering extreme pain requiring relatively fast relief.
Other cholelitholysis procedures include cholesterol contact dissolution techniques in which solvent capable of dissolving cholesterol is brought into direct contact with gallstones having high cholesterol contents. Typically, this procedure is performed using a percutaneous puncture of the gallbladder with specialized catheters. The gallbladder is then continually irrigated with the solvent which is pumped through the catheter and into the gallbladder. During the irrigation process the cholesterol portion of gallstones gradually dissolves and is withdrawn from the gallbladder in the waste solvent. These treatment methods have the advantage of requiring hours instead of months for dissolution and the patient recovery time is considerably shorter than recovery times associated with cholecystectomy.
The most commonly used procedure involves irrigating the gallbladder with solvents having relatively high cholesterol solubility, such as methyl tert-butyl ether (MTBE). Other solvents and solvent combinations which are reported to have been successfully utilized to dissolve cholesterol gallstones include mixtures of fatty acid and/or alcohol esters of fatty acids (U.S. Pat. No. 4,205,086), mixtures of monooctanoin and diethyl ether (U.S. Pat. No. 4,910,223), and mixtures of fatty acid glycerides and a monoterpene such as d-limonene (U.S. Pat. No. 4,767,783).
In addition to the just described cholelitholysis solvent systems, some researchers have reported that quaternary ammonium salts enhance the dissolution rate of cholesterol when used in conjunction with sodium cholate and lecithin in in vitro experiments (Cholesterol Gallstones Dissolution Rate Accelerators I: Exploratory Investigations, Journal of Pharmaceutical Sciences, 66, 8, August 1977, Kwan et al. and Influence of Benzalkonium Chloride on the Dissolution Rate Behavior of Several Solid-Phase Preparations of Cholesterol in Bile Acid Solutions, Journal of Pharmaceutical Sciences, 71, 2, February 1982, Feld et al.)
A major problem associated with all these cholelitholysis systems is their ineffectiveness in dissolving noncholesterol gallstones and the noncholesterol components of cholesterol rich gallstones. Cholesterol gallstones almost always contain materials which are not soluble in solvents typically used to dissolve cholesterol. These noncholesterol components not only appear in cholesterol rich gallstones, but can be the major constituent of gallstones. In cholesterol rich gallstones, the noncholesterol components are primarily in the form of calcium bilirubinate, polymerized bilirubin and calcium carbonate. Of these components, the bilirubinates and polymerized bilirubin are frequently collectively referred to as pigment.
Biliary stones which are primarily pigment generally contain small amounts of cholesterol and the calcium bilirubinate and polymerized bilirubin are generally present within a glycoprotein matrix. These gallstones may also contain additional noncholesterol components including calcium carbonate, calcium phosphate, calcium oxalate and calcium fatty acid salts such as calcium palmitate. Depending upon their appearance, density, hardness, and chemical composition, pigment gallstones can be further classified into brown pigmented and black pigmented stones.
Black pigmented stones are generally less than 3 mm in diameter and have a dark rough surface. They are also comparatively hard with a nodular appearance. Brown pigmented stones are significantly softer than the black pigmented stones or the cholesterol rich stones, are lower in density and have a light brown or tan appearance. Their size tends to vary from about 1 mm to about 10-20 mm and often the brown pigmented stones have different geometrical shapes.
Attempts to dissolve noncholesterol components of cholesterol rich gallstones, as well as attempts to dissolve pigmented stones have met with only limited success. Some researchers have tried to dissolve all components of cholesterol rich gallstones by first directly infusing MTBE into the gallbladder or biliary tree to dissolve the cholesterol portion and then infusing aqueous alkaline solutions of ethylenediaminetetraacetic acid (EDTA) and dimethylsulfoxide (DMSO) in an attempt to dissolve the calcium salts and pigment residue portion. (Dissolving Agents of Human Mixed Cholesterol Stones, K. Y. Dai et al., Gastroenterol Clin Biol, 1988, 12, 312-319). While showing some reduction in the stone residue, these solutions do not effect significant dissolution.
Other researchers have studied the effects of using combinations of bile acids and EDTA alternating with combinations of MTBE and N-acetyl cysteine (Clinical Science, Dowling, 1990, 79 suppl.). Expanding upon the limited ability of EDTA to dissolve calcium and other mineral complexes left after dissolving the cholesterol in mixed gallstones, others have investigated ionic and nonionic surfactants in combination with EDTA. It is generally recognized, however, that while systems incorporating EDTA contribute to the dissolution of calcium complex components of gallstones, they do not always dissolve sufficient quantities of the pigment and other noncholesterol components of gallstones. Accordingly, EDTA solutions are not consistently clinically reliable for the treatment of gallstone disease.
With respect to dissolving pigment gallstones and other forms of calculi which have largely pigment components and lesser amounts of mineral complexes, solutions variously containing EDTA polysorbates, bile salts, N-acetyl cysteine, monoolein, EDTA or DMSO have been investigated. Varying degrees of success in dissolving these forms of calculi have been reported. The amount to which the dissolution is effected by EDTA depends upon the relative amounts of calcium components, and additional chemical considerations involving the composition of the pigment stones. For example, gallstones frequently exhibit alternating layers of cholesterol, and noncholesterol components. EDTA solutions are generally ineffective in dissolving stones having an outer exposed cholesterol layer, even if the stones have a large calcium complex component.
Accordingly, there is a need to provide compositions and methods for dissolving and/or deaggregating various combinations of calcium carbonate, calcium palmitate, calcium bilirubinate, polybilirubinates, and glycoprotein.
There is also a need to provide compositions for dissolving and/or deaggregating on contact the noncholesterol portions of mixed calculi including the noncholesterol portions of cholesterol gallstones.
There is also a need to provide compositions for dissolving and/or deaggregating on contact pigment calculi including both brown and black pigmented gallstones.